Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_002880.3(RAF1):c.775T>A (p.Ser259Thr)

CA261617

40601 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 70e55828-a26c-447c-863d-156419f819e2
Approved on: 2017-04-03
Published on: 2020-04-13

HGVS expressions

NM_002880.3:c.775T>A
NM_002880.3(RAF1):c.775T>A (p.Ser259Thr)
NC_000003.12:g.12604195A>T
CM000665.2:g.12604195A>T
NC_000003.11:g.12645694A>T
CM000665.1:g.12645694A>T
NC_000003.10:g.12620694A>T
NG_007467.1:g.64985T>A
NM_001354689.1:c.775T>A
NM_001354690.1:c.775T>A
NM_001354691.1:c.532T>A
NM_001354692.1:c.532T>A
NM_001354693.1:c.676T>A
NM_001354694.1:c.532T>A
NM_001354695.1:c.433T>A
NR_148940.1:n.1190T>A
NR_148941.1:n.1190T>A
NR_148942.1:n.1190T>A
NM_001354689.3:c.775T>A
NM_001354690.2:c.775T>A
NM_001354691.2:c.532T>A
NM_001354692.2:c.532T>A
NM_001354693.2:c.676T>A
NM_001354694.2:c.532T>A
NM_001354695.2:c.433T>A
NR_148940.2:n.1106T>A
NR_148941.2:n.1106T>A
NR_148942.2:n.1106T>A
ENST00000251849.8:c.775T>A
ENST00000416093.1:c.*353T>A
ENST00000423275.5:c.*452T>A
ENST00000432427.2:n.412T>A
ENST00000442415.6:c.775T>A
ENST00000465826.5:n.19T>A
ENST00000491290.1:n.296T>A
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Pathogenic

Met criteria codes 9
PS4_Supporting PS3 PP1 PP3 PP2 PM6_Strong PM2 PM1 PM5_Strong

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.775T>A (p.Ser259Thr) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; APHP-Robert Debré Hospital internal data; GTR ID's: 28338). The p.Ser259Thr variant has been identified in at least 8 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381 PMID: 21784453; ClinVar SCV000061360.5; SCV000209017.10). The p.Ser259Thr variant in RAF1 has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 506381; ClinVar SCV000209017.9). In vitro functional studies provide some evidence that the p.Ser259Thr variant may impact protein function (PS3; PMID: 21784453, 20052757). At least 2 other pathogenic missense variants have been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40603, 40602, 228288). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser259Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Supporting, PP1, PM5_Strong, PM2, PM1, PP2, PP3, PS3.
Met criteria codes
PS4_Supporting
The p.Ser259Thr variant has been identified in at least 8 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381 PMID: 21784453; ClinVar SCV000061360.5; SCV000209017.10).
PS3
In vitro functional studies provide some evidence that the p.Ser259Thr variant may impact protein function (PS3; PMID: 21784453, 20052757).
PP1
The p.Ser259Thr variant in RAF1 has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Zenker et al. internal data; ClinVar SCV000209017.9).
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581).
PM6_Strong
The c.775T>A (p.Ser259Thr) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; APHP-Robert Debré Hospital internal data; GTR ID's: 28338).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).
Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). PubMed:29493581
PM5_Strong
At least 2 other pathogenic missense variants have been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40603, 40602, 228288).
Curation History
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